基于非线性光学成像的慢性乙肝肝纤维化进展/逆转的量化结构特征参数的研究

Liver fibrosis is the basic histopathological consequence of chronic hepatitis B (CHB). It has been validated by the longitudinal studies that the degree of liver fibrosis is the major prognostic risk factor for the final clinical outcomes of CHB. However, the current clinical evaluation systems for fibrosis assessment cannot provide the accurate and precise information of progression/regression of liver fibrosis, which is urgently required by the modern therapeutics for CHB disease. Based on the systematic reviewing of the current progress in the relevant theory of structure-function interactions and the research and development of liver fibrosis evaluation methods, and the supportive results from our preliminary research as well, we hypothesize that the complete histological information of fibrosis, including both the relevant structural items and their quantitative values, could have the potential to more precisely and accurately predict the dynamics of fibrosis development than the current systems do. Therefore, employing the adequate clinical resource of CHB therapy in our institution and the specific technological strength of our research team, the present project plans to, use the nonlinear optical technology, second harmonic generation microscopy (SHG) to collect the quantifiable raw imaging data of CHB liver tissue sample; extract the candidates of structural features out of them, with reference to the recognized histological characteristics of CHB; and then taking the parameter data, which are generated from the endpoints for the relevant clinical outcomes, as the comparing standard, select, optimize and establish the panel of structural-featured markers for the evaluation of liver fibrosis, and assess its performance of predictability by statistical analysis. The proposed study will not only initiate a novel strategy for the methodology of fibrosis evaluation, but also provide a potentially valuable diagnostic tool which is inherent of the objective and truly-quantitative approach for the modern CHB therapeutics.

肝纤维化是慢性乙型病毒性肝炎(CHB)组织病理学的基本特征。长期临床研究证明,肝纤维化程度是影响CHB预后的主要危险因素。但是目前肝纤维化评价系统已不能满足现代治疗学对于精准评判CHB肝纤维化进展/逆转（P/R）的临床需求。回顾分析相关理论和国内外研究进展，并结合本项目前期实验结果，我们提出假说：完整的组织学信息（包括纤维化结构特征及其数量关系）能更精准地反映和预测肝纤维化P/R临床变化。由此，基于依托单位临床资源和团队技术特色，我们将利用非线性光学二次谐波成像技术，采集CHB肝纤维化的原始组织学信息；参考肝组织学规律，提取并量化其中结构特征参数；以相关临床终点数据为对照指标，运用统计学分析，优化建立该参数模型评价系统；并验证其临床评价能力。本项目的实施不仅会为肝纤维化分析的方法学研究提供新思路；而且还将为现代CHB治疗学提供以客观性和连续性量化数据为基本特点的新型肝纤维化辅诊工具。

慢乙肝及相关肝病是全球尚未解决的重大公共健康问题。肝纤维化是慢性肝损伤过程中病理性组织修复的特征表现。大量临床研究证明，肝纤维化是影响慢乙肝个体化诊治和疾病进展预后评估的重要指标。在当前抗病毒治疗学普遍进步的情况下，这一指标对临床实践的指导价值更加突出，但是尚缺乏量化客观精准评价肝纤维化进展/逆转变化的相关指标参数和技术工具。本项目提出假说：完整的组织学信息（包括纤维化结构特征及其数量关系）能更精准地反映和预测肝纤维化临床变化。因此研究目的是，探索基于二次谐波新型成像技术获得纤维化非染色组织学参数，鉴定全量化组织学参数对慢乙肝肝纤维化的分析能力，以此建立对慢乙肝肝纤维化动态变化具有精准描述能力的新型全定量评价系统。本研究采取依托临床队列研究，临床基础研究相结合的方式，验证了此创新量化组织学新概念解决临床问题的科学性、可行性和有效性。包括，基于二次谐波新型成像技术，获得肝纤维化组织中胶原纤维的量化结构特征信息；基于慢乙肝组织学演变特点，对胶原纤维的结构特征参数进行分类与建模；基于初步验证的量化组织学参数定义，对慢乙肝多中心随机对照临床试验队列样本的肝纤维化动态变化程度进行个体化分析，对照目前临床肝纤维化组织学诊断标准，检验全量化组织学参数的测量能力和特点；针对慢乙肝肝硬化阶段的特殊组织学和临床特点，研制了肝硬化组织学特征定量分析新参数工具，并在双向动物疾病模型和慢乙肝肝硬化组织学样本完成验证。以上内容就当前慢乙肝肝纤维化组织学精准测量研究，初步验证了本项目科学假说并形成了比较完整的慢乙肝肝纤维化新型量化组织学分析体系。本研究建立的这种对慢乙肝肝纤维化动态变化具有精准描述能力的新型全定量指标参数及其评价系统，不仅为肝纤维化分析的方法学研究提供新思路，有望协助解决病理诊断方法的瓶颈问题；还将会作为新型生物技术工具，有助于推动慢乙肝肝纤维化有效防治的临床与基础生物医药研究不断进步。